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Cell:运载RNA进入线粒体的蛋白被发现

放大字体  缩小字体 发布日期:2010-08-09  来源:Cell  浏览次数:4999
核心提示:加利福利亚大学洛杉矶分校Jonsson综合癌症中心的研究人员发现了能将RNA运入线粒体的蛋白。
 (Credit: Maureen Heaster)
  
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        加利福利亚大学洛杉矶分校Jonsson综合癌症中心的研究人员发现了能将RNA运入线粒体的蛋白。
 
  将细胞核编码的小RNA运入线粒体,这一过程对线粒体基因组的复制,转录和翻译是非常重要的,但此前对运送RNA进入线粒体的机制知之甚少。
 
  UCLA的科学家们发现了一种叫做多核苷酸磷酸化酶(PNPASE)的蛋白,它在调节RNA进入线粒体时发挥作用。当减少PNPASE的表达时会降低RNA的进入,这会影响线粒体基因组编码RNA的过程。而这会影响维持电子传递连所需蛋白的合成。当降低PNPASE表达时,未经加工的线粒体RNA会积聚起来,蛋白翻译会受抑制,能量的产生受到阻碍,这将导致细胞生长的停滞。
 
  此项研究发表在2010年8月5日的Cell杂志上。
 
  据研究者介绍,这项研究中发现,PNPASE能够通过介导胞质RNA的运输来调节线粒体产生能量的。此研究使得人们对基础层次的细胞功能有了新的认识,这为通过调节线粒体产能并进而控制细胞(包括一些种类的癌细胞)生长提供了新的手段。
 
  线粒体常被描述成细胞内的发电厂,因为它们产生绝大多数细胞所需的能量。除了提供能量,线粒体也参与了多种细胞过程,包括信号,分化,死亡,对细胞周期和生长的控制。
 
  这项研究有可能对一些癌症的治疗产生影响,这些癌症的生长和扩散是依赖细胞能量的,还有可能为一些诸如神经肌肉疾病的线粒体功能紊乱引起的疾病提供治疗思路。这项研究也可能引起对一些神经退行病变引起疾病的心的思索,诸如帕金森氏症和阿尔兹海默氏症,近期研究表明这些疾病与线粒体功能有关。
 
  据研究者介绍,当讨论癌症疗法时,首先要弄起什么使细胞生长和死亡,而线粒体,正是这个问题的核心所在。目前这条RNA进入线粒体的新通路的发现,为研究线粒体在正常胜利条件下和一些疾病中的广泛而重要的作用提供了思路。如果能知道健康细胞中这条通路是怎么起作用的,我们就能够发现是什么使正常细胞变成了癌细胞。
 

Protein That Shuttles RNA Into Cell Mitochondria Discovered

ScienceDaily (Aug. 8, 2010) — Researchers at UCLA's Jonsson Comprehensive Cancer Center and the departments of Chemistry and Biochemistry and Pathology and Laboratory Medicine have uncovered a role for an essential cell protein in shuttling RNA into the mitochondria, the energy-producing "power plant" of the cell.

 

The import of nucleus-encoded small RNAs into mitochondria is essential for the replication, transcription and translation of the mitochondrial genome, but the mechanisms that deliver RNA into mitochondria remain poorly understood.

In the current study, UCLA scientists show a new role for a protein called polynucleotide phosphorylase (PNPASE) in regulating the import of RNA into mitochondria. Reducing the expression of PNPASE decreased RNA import, which impaired the processing of mitochondrial genome-encoded RNAs. Reduced RNA processing inhibited the translation of proteins required to maintain the electron transport chain that handles oxygen to produce energy in the form of adenosine triphosphate, the energy currency of a cell. With reduced PNPASE, unprocessed mitochondrial RNAs accumulated, protein translation was inhibited and energy production was compromised, leading to stalled cell growth.

The study appears Aug. 5, 2010, in the peer-reviewed journal Cell.

"This discovery tells us that PNPASE regulates the energy producing function of mitochondria by mediating cytoplasmic RNA import," said Dr. Michael Teitell, a professor of pathology and laboratory medicine, a Jonsson Cancer Center researcher and co-senior author of the study. "The study yields new insight for how cells function at a very fundamental level. This information provides a potential new pathway to control mitochondrial energy production and possibly impact the growth of cells, including certain types of cancer cells."

Mitochondria are described as cellular power plants because they generate most of the energy supply of the cell. In addition to supplying energy, mitochondria also are involved in a broad range of other cellular processes, such as signaling, differentiation, death, control of the cell cycle and growth.

The study could have implications for studying and treating certain cancers, which rely on cellular energy to grow and spread, as well as mitochondrial disorders such as neuromuscular diseases. The study could also result in new ways to think about attacking neurodegenerative disorders, such as Parkinson and Alzheimer diseases, which have recently been linked to the function of mitochondria.

"When we're talking about looking for ways to cure cancer, we fundamentally need to understand what makes cells grow and die and the mitochondrion is right at the heart of these issues," said Carla Koehler, a professor of chemistry and biochemistry, Jonsson Cancer Center researcher and co-senior author of the study. "This new and novel pathway for transporting RNA into the mitochondria is shedding new light on the evolving role and importance of mitochondria function in normal physiology and a wide variety of diseases. If we can understand how this pathway functions in healthy cells we could potentially uncover defects that help in transforming normal cells into cancer cells."

PNPASE was identified in 2004 by Teitell and his team as they attempted to find proteins that interact with TCL1, a human lymphoma-promoting cancer gene that has been used to generate genetic models of lymphocyte cancer. Mass spectrometry uncovered PNPASE, which had a signature sequence that suggested that it trafficked into and localized within the mitochondria of cells.

Once localized, Teitell, Koehler and post-doctoral fellow Geng Wang turned their attention to the function of PNPASE, which generated the unexpected results reported in this study. Prior to their discovery, it was not known what pathway was used to get RNA into the mitochondria. PNPASE mediates the movement of RNA from the cell cytoplasm, the area of the cell enclosed by the cell membrane, into the matrix of mitochondria, where the mitochondrial genome is located. The protein acts as receptor and binds to cytoplasmic RNAs that have a particular stem-loop signature sequence, mediating import, Teitell said.

Without this RNA import, the cell lacks the machinery to assemble the mitochondria's energy source, Koehler said.

"The cell would lose most of its ability to make energy," she said. "It would be crippled. Mitochondria are fantastically complex and our study reveals another cellular pathway in which these tiny but important powerhouses participate in essential cell activities, such as the generation of energy essential for life."

The study was funded by the National Institutes of Health, the California Institute for Regenerative Medicine, the American Heart Association, the Leukemia & Lymphoma Society and a NIH Nanomedicine Roadmap Grant.

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Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of California - Los Angeles, via EurekAlert!, a service of AAAS.
 

Journal Reference:

  1. Geng Wang, Hsiao-Wen Chen, Yavuz Oktay, Jin Zhang, Eric L. Allen, Geoffrey M. Smith, Kelly C. Fan, Jason S. Hong, Samuel W. French, J. Michael McCaffery, Robert N. Lightowlers, Herbert C. Morse, Carla M. Koehler, Michael A. Teitell. PNPASE Regulates RNA Import into Mitochondria. Cell, 2010; DOI: 10.1016/j.cell.2010.06.035


关键词:多核苷酸磷酸化酶 PNPASE 线粒体 癌症
 
 
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